title: A mechanism underlying hypertensive occurrence in the metabolic syndrome: cooperative effect of oxidative stress and calcium accumulation in vascular smooth muscle cells.
abstract: Several lines of evidence indicate that reactive oxygen species (ROS) overproduction under the metabolic syndrome condition is the leading cause of cardiovascular events. Calcium is an important stimulus for vasoconstriction and plays a pivotal role in the development of hypertension. Here, we investigate whether a relationship exists between metabolic syndrome-induced mitochondrial ROS overproduction and Ang II-mediated Ca2+ release in vascular smooth muscle cells (VSMC). The effect of mitochondrial ROS on AT1 expression, and Ca2+ and IP3 generation was studied in 2 VSMC models of metabolic syndrome using fura-2/AM probes and ELISA-based assay. Ang II-mediated aortic ring contraction in SD rats fed with high-fat diet (HFD) was measured using a force transducer connected to chart recorder. In the metabolic syndrome, almost 2-fold increased mitochondrial O2 - significantly upregulated AT1 expressions by ~60%, companied by elevated Ca2+ and IP3 levels in VSMC and enhanced aortic rings contraction. All these increments were blocked by rotenone (inhibitor of mitochondrial respiratory chain complex I), ruthenium red (inhibitor of calcium uniporter), cyclosporin A (inhibitor of mitochondrial permeability pore), and N-acetylcysteine. Therefore, in the states of metabolic syndrome, ROS overproduction in mitochondrial complex I enhances Ang II-mediated vascular contraction via an AT1-dependent pathway. In addition, the import of Ca2+ from endoplasmic reticulum to mitochondria via calcium uniporter and mitochondrial permeability pore seems to serve as a mechanism to further aggravate mitochondrial damage and vascular dysfunction that may contribute to the occurrence of hypertension.
authors.affiliation: Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: S M
authors.initials: SM
authors.lastname: Yan
authors.affiliation: Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: H L
authors.initials: HL
authors.lastname: Zheng
authors.affiliation: Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: D H
authors.initials: DH
authors.lastname: Hu
authors.affiliation: Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Y T
authors.initials: YT
authors.lastname: Zhang
authors.affiliation: Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Q H
authors.initials: QH
authors.lastname: Guan
authors.affiliation: Experimental and Teaching Center of Medical Basis for Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Q L
authors.initials: QL
authors.lastname: Ding
mesh_terms: D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D059305:Diet, High-Fat / Q000009:adverse effects; D006973:Hypertension / Q000209:etiology*; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000503:physiopathology*; D008931:Mitochondria, Muscle / Q000737:chemistry / Q000378:metabolism; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D013481:Superoxides; D000804:Angiotensin II; D013482:Superoxide Dismutase; D002118:Calcium